DIRECTORATE OF LEARNING SYSTEMS

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1 DIRECTORATE OF LEARNING SYSTEMS DISTANCE EDUCATION PROGRAMME INTEGRATED HIV/AIDS PREVENTION, TREATMENT AND CARE Unit 5 Antiretroviral Therapy in Adults and Adolescents The Allan and Nesta Ferguson Trust

2 Unit 5: Antiretroviral Therapy in Adults and Adolescents A distance learning course offered by the AMREF Directorate of Learning Systems 2007 African Medical Research Foundation (AMREF) This course is distributed under the Creative Common Attribution-Share Alike 3.0 license. Any part of this unit including the illustrations may be copied, reproduced or adapted to meet the needs of local health workers, for teaching purposes, provided proper citation is accorded AMREF. If you alter, transform, or build upon this work, you may distribute the resulting work only under the same, similar or a compatible license. AMREF would be grateful to learn how you are using this course and welcomes constructive comments and suggestions. Please address any correspondence to: The African Medical and Research Foundation (AMREF) Directorate of Learning Systems P O Box , Nairobi, Kenya Tel: +254 (20) Fax: +254 (20) amreftraining@amrefhq.org Website: Writer: Dr Jared Mecha Cover Design: Bruce Kynes Technical Co-ordinator: Joan Mutero The African Medical Research Foundation (AMREF) wishes to acknowledge the contributions of the Commonwealth of Learning (COL) and The Allan and Nesta Ferguson Trust whose financial assistance made the development of this course possible.

3 Contents Unit 5: Introduction... 1 Unit Objectives... 1 Section 1: Introduction to Antiretroviral Agents Introduction... 2 Classification of ARVs... 2 Mode of Action and Side Effects of ARVs... 5 Goals of Antiretroviral Therapy (ART) What Are The Limitations of ART? Summary Section 2: Initiating ARVs in Adults and Adolescents Introduction Rationale For ART Initiation Benefits of delayed therapy Risks of delayed therapy Criteria for Starting ARV Therapy Other Requirements for Starting ART Patient Assessment and Education Prior to ART Initiation Choosing a ARV Regimen Starting Treatment in People With Tuberculosis and HIV Co-Infection Summary Section 3: Monitoring of ART in Adults and Adolescents Introduction Monitoring and Follow-up of Patients on Antiretroviral Therapy Monitoring Treatment Monitoring efficacy and side effects of treatment Changing Therapy Discontinuation of Therapy Summary... 58

4 Acronyms and Abbreviations 3TC Lamivudine ABC Abacavir AIDS Acquired immune deficiency syndrome ANC Antenatal care ART Antiretroviral therapy ARV Antiretroviral AZT Zidovudine C&T Counseling and testing C&S Culture & sensitivity CNS Central nervous system CSF Cerebrospinal fluid CBC Complete blood count d4t Stavudine ddc Zalcitabine ddi Didanosine DLV Delavirdine DFID Department for International Development DOT Directly observed treatment DOTS Directly observed treatment strategy EBV Epstein-Barr virus EHRZ ethambutol (E), isoniazid (H), rifampicin (R), pyrazinamide EFZ Efavirenz (Z) HAART Highly active antiretroviral therapy HSV Herpes simplex virus INH Isoniazid KS Kaposi s sarcoma mg Milligram mg/l Milligrams/liter NAM Nucleoside analogue mutation NFV Nelfinavir NNRTI Nonnucleoside reverse transcriptase inhibitor NSAID Nonsteroidal anti-infl ammatory drug NRTI Nucleoside reverse transcriptase inhibitor NVP Nevirapine NsRTI Nucleoside reverse transcriptase inhibitor PZA Pyrazinamide RIF Rifampin RNA Ribonucleic acid RTV Ritonavir SHRZE Streptomycin (S), Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E) STD Sexually transmitted disease TB Tuberculosis TDF Tenofovir TLC Total lymphocyte count

5 Unit 5: Introduction Welcome to the fifth Unit in our course on Integrated HIV/AID Prevention, Care and Support. In the last unit we discussed the common HIV Associated Conditions. In this unit we shall look at antiretroviral therapy in adults and adolescents. We shall introduce you to antiretroviral agents (their classification, modes of action and common side effects) and discuss their rational use in the management of HIV/AIDS in resourcelimited settings. But first, let us look at our objectives for this unit. Unit Objectives By the end of this unit you should be able to: Describe the classification and mode of action of ARVs; Discuss the goals of antiretroviral therapy; Describe the rationale for standard treatment regimens; Describe the characteristics of widely used ARVs; Discuss the rationale and timing for ART initiation; Describe the preparation of a patient for ART; Explain the common side-effects associated with ARVs and discuss strategies to minimize/manage these side effects; Describe the common drug interactions between ARVs and drugs commonly used in the management of HIV disease; Discuss the follow-up of patients on ART; Discuss the common reasons for treatment failure, changing of ART regimens and stopping ART. The Unit is made up of three sections. Section 1 will look at classification,,mode of action of antiretroviral agents. Section 2 will discuss how to initiate ARVs in adults and adolescents, while Section 3 will look at how to monitor ART side-effects of ART, drug interactions, adherence and when to stop or change the ART regimens. 1

6 Section 1: Introduction to Antiretroviral Agents. Introduction Welcome to the first section of this unit. In this section we shall discuss the classification, mode of action, goals, benefits and limitations of ART. You will recall in Unit 1 Section 2, we discussed the biology of the HIV virus. Can you remember what we said? We said that the HIV disease is caused by a retrovirus which enters human cells (CD4+ T-lymphocytes) and uses them as a factory to reproduce itself. Like all disease causing pathogens, HIV has a life-cycle. Knowledge of this life cycle is core to understanding the mechanism of action of antiretroviral drugs. This is because the drugs used in HIV treatment target essential steps in the HIV life cycle by either blocking the step or inhibiting the enzyme required to catalyze the step. Let s start by reviewing our objectives for this section. Section Objectives By the end of this section you should be able to: Describe the classification of ARVs; Explain their mode of action; Discuss the goals, benefits and limitations of antiretroviral therapy. Let s start by looking at how ARV drugs are classified. Classification of ARVs HIV is a retrovirus. So drugs against HIV are called anti-retroviral drugs or ARV in short. When we give ARV drugs in the correct way, with adherence support, this is called Antiretroviral Therapy or ART in short. In Unit 1 you learnt about the HIV life cycle. Can you remember the various steps in the life cycle of the virus, and how each step is accomplished? Look at Figure 1.1 on the HIV life cycle to refresh your memory. 2

7 Figure 1.1: HIV life cycle As you can see from this figure, HIV attaches itself to the CD4+ lymphocyte is through the CD4 receptor on the surface of the lymphocyte. The first drug that could inhibit HIV replication was zidovudine (AZT or ZDV). It was first used in the treatment of HIV infection in Since then, more than 25 agents have been developed that are active against HIV replication. 3

8 There are 3 main groups of antiretroviral drugs available for clinical use depending on their site of action on the HIV replication cycle. These are: Reverse transcript inhibitors o Nucleoside reverse transcriptase inhibitors (NRTI) o Nucleotide reverse transcriptase inhibitors (NtRTI) o Non-nucleoside reverse transcriptase inhibitors (NNRTI) Protease inhibitors. Entry Inhibitors This is a new class of antiretroviral drugs. They are at times referred to as fusion inhibitors. These antiretroviral agents work at different steps as shown in Figure 1.2 below, to block HIV from making new copies of itself inside the cell or assembling its various parts to form a new virus. Targets of ARV drugs gp41 gp120 Viral assembly NRTI s& NNRTI s work here Fusion inhibitors work here Injection of contents RNA s e CD4 Cell HOST CELL Reverse transcription RNA DNA Transcription Provirus (circular structure) Translation Protein cleavage Protease Integrase Budding Protease Inhibitors work here Maturation Integration of provirus DNA into host DNA HIV Particle HIV particle Binding Binding sites Cell membrane Completed HIV particle Figure 1.2: Targets of ARV drugs 4

9 Mode of Action of ARVs As we mentioned earlier there are three main groups of ARVs available for clinical use. These are: Reverse Transcriptase Inhibitors; Protease inhibitors Entry Inhibitors We shall now look at their mode of action. Reverse Transcriptase Inhibitors As you can see from Figure 1.1, HIV enters the CD4 lymphocyte together with genome (composed of ribonucleic acid, RNA), and several enzymes which are essential for its replication. One such enzyme is reverse transcriptase (RT), which is needed immediately the virus enters the cell. The function of reverse transcriptase is to copy (transcribe) viral RNA to viral DNA. This step is essential before the virus can be integrated into the human cell nucleus (made up of DNA). Normally, RNA is made from DNA, however, HIV reverses this process and starts making DNA from RNA through the use of this special enzyme reverse transcriptase. There are 3 classes of reverse transcriptase inhibitors (RTIs) namely: 1. Nucleoside reverse transcriptase inhibitors (NRTI) 2. Nucleotide reverse transcriptase inhibitors (NtRTI) 3. Non-nucleoside reverse transcriptase inhibitors (NNRTI) Initially, the names of these classes appear strange, like they are designed NOT to be remembered! But it is actually quite simple. A reverse transcriptase inhibitor is named depending on whether or not it contains a molecule similar to the naturally occurring nucleotides (adenine, thymine, cytosine, and guanine). If it does, it is a nucleoside analogue, if it does not, it is a non-nucleoside. 5

10 1. Nucleoside reverse transcriptase inhibitors (NRTIs) These agents act as fake nucleosides in the cell. They compete with the true nucleosides when viral DNA is being formed. The DNA formed containing these fake nucleosides is thus abnormal and therefore viral replication is prevented. The table below has examples of the common NRTIs, with their dosages and side effects. Table 1.1: Nucleoside analogue Reverse Transcriptase Inhibitors (NRTIs) Drug Dose (adults)* Common and Important Side effects Zidovudine >12 years, 300 mg Anaemia, leucopenia (low (AZT, ZDV) BD white cell counts), thrombocytopenia (low platelets-can cause bleeding) Lamivudine (3TC) Stavudine (d4t) >37.5 kg 150 mg BD Very well tolerated. May be associated with hepatitis <30 kg: 30 mg BD Peripheral neuropathy >40 kg: 40 mg BD (numbness, tingling/burning sensations, weakness), fat redistribution in the body Abacavir (ABC) >37.5 kg or over 16 years: 300 mg BD Didanosine (ddi) Emtricitabine (FTC) <60 kg, 250 mg/day >60 mg, 400 mg/day Used in combination with tenofovir as a fixed dose preparation taken once daily (lipodystrophy) Hypersensitivity (fever, rash, cough, difficult breathing) Pancreatitis (suspect if has abdominal pain, nausea, vomiting) and peripheral neuropathy Well tolerated Comments Requires monitoring of haemoglobin and white cell count regularly during use. Has no food restrictions No food restrictions No food restrictions. Should not be used with zidovudine Patients and carers should be educated on the possibility of sensitivity reaction. Patient should not be re-started on ABC after a hypersensitivity reaction To be taken on an empty stomach half hour before food, OR two hours after a meal Very similar to 3TC No food restrictions *Almost all NRTIs require dose adjustment in case of renal or liver disease. Tenofovir is a nucleotide analogue reverse transcriptase inhibitor (NtRTI). It is used at a dose of 300 mg once daily and is well tolerated. It should be taken with a meal. 6

11 2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) These drugs bind directly to the reverse transcriptase enzyme and therefore inhibit its activity. They prevent the conversion of RNA to DNA. Table 1.2 lists the drugs and dosages for this class of drugs. Table 1.2: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Name and class of drug Strength of preparation Adult dosing Efavirenz (EFZ) Capsules, 200mg, tablets 600mg 600mg OD Navirapine (NVP) Tablets, 200mg 200mg BD Delavirdine (DLV) Capsules, 100mg 600mg OD Two agents in this class are commonly used: Nevirapine and efavirenz. Nevirapine It is not affected by meals and may be taken with or without food. The main side effects of Nevirapine are a skin rash that may occur in 15 to 30% of patients. In about 7%, this rash is severe and extensive and is life threatening, which necessitates that the drug be stopped and never used again in that patient. In some patients, Nevirapine may cause hepatitis. It is therefore very important to monitor a patients liver enzymes when they are on this drug. At initiation of therapy, Nevirapine is started at a lower dose of 200mg for the first 2 weeks to reduce the risks of severe liver side effects and severe skin rash. If tolerated the dose is increased to 200 mg twice daily. When used in combination with certain drugs, the likelihood of liver injury increases. For this reason, Nevirapine should not be used together with rifampicin. Patients with TB who are on a rifampicin-containing regimen should be given efavirenz instead of nevirapine. Nevirapine should not be used together with rifampicin. Patients with TB who are on a rifampicin-containing regimen should given efavirenz instead 7

12 Effavirenz This is a relatively safe drug in comparison with nevirapine, though it is more costly. It is also easier to administer, as it only requires one dose per day. Its absorption is markedly improved when taken with a fatty meal, as are its side effects. The commonest side effect of effavirenz is dizziness. The drug is therefore prescribed for bed time. It may also cause abnormal dreams, loss of sleep, increased sleepiness, confusion, hallucinations and poor concentration. These side effects usually disappear after two to four weeks of consistent use. Effavirenz may occasionally cause a rash. In pregnancy, this drug should not be used as it has been associated with increased risk of congenital malformations in experimental animals. Female patients in the reproductive age group who are on effavirenz should be on contraceptives. It is given at a dose of 600 mg once daily (preferably at bed-time). Nucleotide Reverse Transcriptase The only drug in this class is Tenofovir. Its mechanism of action is similar to that of NRTI S. Next let us look at the second group of antiretroviral drugs, namely protease inhibitors. Protease Inhibitors (PIs) Protease Inhibitors work at the last stage of the virus reproduction cycle. They prevent the HIV virus from being successfully assembled and released from the infected cell. The viral enzyme, protease, is responsible for assembling and maturing newly formed viral proteins into a viable virus capable of infecting new cells. When the central part of the body cell makes parts of the HIV virus after infection, these parts have to be cut and put together in the right way before the new HIV copies can leave the cell. Protease inhibitors prevent this cut and putting together from happening correctly. Thus the newly produced virus parts cannot leave the infected cell and infect other cells. PI drugs block the special substance HIV uses to put the different parts together to form a new HIV virus before it leaves the cell. 8

13 Protease Inhibitors in clinical use include the following drugs: Indinavir: This may cause renal stones formation. Advise patients to take at least 2 litres of water per day. It should not be taken at the same time as didanosine. If it must, make sure that you separate the two by 2 hours, to make sure it is taken on an empty stomach. Ritonavir: used in small doses to boost other PIs; requires refrigeration if stored for more than 30 days. The oral solution contains 12% alcohol. Saquinavir. Nelfinavir; main side effect is diarrhoea. Should be taken with a fatty meal to improve bioavailability. Lopinavir: Boosted with ritonavir (i.e. Kaletra), requires refrigeration, when in storage for more than 2 months, otherwise stable at 25 o C for less than 2 months. Amprenavir. Forsamprenavir Atazanavir Table1.3: Protease Inhibitors Name and class of drug Strength of preparation Adult dosing Saquinavir hard-gel (SQV) Capsules, 200mg 600mg OD Saquinavir soft-gel (SQV) Capsules, 200mg 1200mg OD Ritonavir** (RTV) Capsules, 100mg 600mg OD Indinavir (IDV) Capsules, 200mg 800mg TID Nelfinavir** (NFV) Tablets 250mg 1250mg BD or 750mg TDS Amprenavir^ (AMV) Tablets, 300mg 1200mg BD Lopinavir + Ritonavir^ Capsules (133mg Lopinavir mg Ritonavir) 400mg Lopinavir + 100mg Ritonavir BD Drugs marked * are not available in Kenya and drugs marked ** are available in paediatrics formulations. Absorption of PI s is enhanced by a high fat diet. Once absorbed, they are metabolized by the liver and mainly excreted through faeces, though a small percentage is eliminated by the kidneys. 9

14 Common side effects of PI S include: Lipodystrophy: this refers to the redistribution of body fat in which fat from the peripheral parts of the body is lost. This is accompanied by deposition of fat over the central parts of the body, mainly over the abdomen, breasts, upper back and subcutaneous tissue; Glucose intolerance: this results in poor glucose control and may be associated with an increased risk of diabetes; Elevated blood cholesterol; Gastro intestinal tract intolerance; Elevated liver enzymes. These drugs are often reserved for use as second-line drugs in patients whose initial regimen is failing. No antiretroviral drug or combination of drugs can completely eliminate HIV from the body. Additionally, most of the available agents have potential serious side effects and complicated dosing schedules. Therefore, the search for safer and more effective antiretroviral agents continues. Table 1.4 below gives the drugs available in Kenya. Table 1.4: Commonly used antiretroviral drugs in Kenya NRTI NNRTI PI Nucleoside reverse transcriptase inhibitors Nucleotide reverse transcriptase inhibitor Non-nucleoside reverse transcriptase inhibitors (NNRTI) Protease Inhibitors (PI) stavudine (d4t) lamivudine (3TC) zidovudine (AZT) didanosine (ddi) abacavir (ABC) emtricitabine (FTC) tenofovir disoproxil fumarate (TDF) nevirapine (NVP) efavirenz (EFV) * ritonavir is used as a helper for another PI, to make the effect of the other PI stronger. lopinavir (LPV) with ritonavir (RTV) as a FDC* nelfinavir (NFV) saquinavir (SQV) Atazanavir (ATV) Having looked at the types of ARV drugs and their mode of action, lets now discuss the goals of this therapy, its benefits as well as its limitations. 10

15 Entry or Fusion Inhibitors This is a new class of Antiretroviral drugs. They are at times referred to as fusion inhibitors. They function by stopping the virus from entering the CD4+ cell. Do you recall the lesson on the pathogenesis of HIV infection? During this lesson, it was mentioned that the HIV virus attacks the CD4+ cell. Well, the entry inhibitors prevent this process, by preventing the virus from entering the cell. An example of the Fusion inhibitors is Enfurvitide (T-20) Goals of Antiretroviral Therapy (ART) While many drugs are available for the treatment of HIV disease, none can cure HIV (i.e. completely eliminate HIV from the body). As you have seen, ARVs work by reducing viral replication (multiplication) thereby reducing the amount of virus in the body. This slows down the destruction of the immune system and other negative effects to other vital body organs. ART should be part of a comprehensive program that encompasses other aspects of care like nutritional support, opportunistic infections prophylaxis, ongoing psychosocial support and prevention of HIV transmission. Because ARVs do not cure HIV infection, treatment is life-long. It should therefore be carefully planned and discussed with the patient. Efficacy of ART can only be assured if there is strict adherence to the prescribed regimen. Regular follow-up and monitoring of treatment is required. What Are The Goals of ART? Before you read on, do the following activity. It should take you less than 5 minutes. ACTIVITY Write down the goals of ART therapy? 11

16 I hope your answer included the following goals of ART: Restoration and preservation of immune function: ART, by reducing the viral load decreases the killing of CD4 cells by HIV. As the number of these cells increases, this protects the patient from opportunistic infections and other HIV associated conditions. Reduce the viral load as much as possible, for as long as possible, in order to halt disease progression and prevent or reduce resistant variants. The key to achieving maximal viral suppression is though the use of at least 3 effective ARV drug combinations (also called highly active antiretroviral therapy-haart), and the patient s adherence to medication. Improved quality of life: patients with HIV disease experience regular infections and other HIV related conditions that require medication and regular hospitalization, pain and discomfort, weight loss, absence from work and social activities etc. The sum effect of these conditions is to adversely affect the quality of life of PLWAs. ART, by reversing these negative effects of HIV-infection, positively influences the quality of life of patients, once again giving them the opportunity to lead normal lives. Reduction in HIV-related mortality and morbidity. How can these goals be achieved? You can achieve these goals through: Providing patient education, assessment and preparation prior to treatment initiation and continued support during treatment. Becoming knowledgeable and experienced in HIV care Adherence to treatment guidelines and best practice. 12

17 ACTIVITY What do you think are the benefits of ARVs? List them down. I hope your list included the following benefits of ARTs: They prolong life and improves quality of life; Households can stay intact; There is a decrease in the number of orphans; They reduce mother-to-child transmission; There is decreased stigma surrounding HIV infection since treatment is now available; Less money is spent to treat opportunistic infections and provide palliative care; They make HIV testing and counselling acceptable to more people; There is increased awareness in the community, since more people get tested; There is increased motivation of health workers, since they feel they can do more for HIV patients; Businesses can stay intact; They reduces absenteeism from work due to illness. 13

18 What Are The Limitations of ART? The limitations of ART include the following: Antiretroviral therapy does not eliminate the virus and so there is no cure for HIV/AIDS. Treatment is life-long. Emergence of resistant HIV strains frequently occurs in particular if patients have poor adherence to therapy. More than 95% adherence is needed to achieve maximal suppression of the virus. Side effects, though not severe, occur with almost all the antiretroviral drugs. Serious complications that lead to discontinuation of treatment may also occur. Sexual transmission of HIV may continue to occur even if the viral load is at undetectable levels in serum. Sexual transmission of multi-drug resistant viral strains has already been documented. Summary Well, we have come to the end of this section. In this section we have looked at the classification of antiretroviral therapy, its mode of action, benefits as well as its limitations. I hope you now understand how ARVs work by intervening in the life cycle of HIV. Before you move on to the next section find out how much you still remember by doing the following activity. ACTIVITY Name two main enzymes which current ARV drugs inhibit? The two enzymes are: Reverse Transcriptase, at the beginning of the Life Cycle Protease, at the end of the life cycle 14

19 If you got this answer right, well done! If not, we suggest that you revise this section again. In the next section we shall discuss how to initiate and monitor ARVs in adults and adolescents. 15

20 Section 2: Initiating ARVs in Adults and Adolescents. Introduction Welcome to the second section of our unit on antiretroviral therapy. In the last section we discussed the classification of ARVs in HIV, their mode of action, benefits as well as limitations. In this section we shall explore how to initiate ARV therapy in adults and adolescents. Section Objectives By the end of this section you should be able to: Discuss the rationale for ART initiation; Describe how to initiate ART treatment; Discuss the considerations of ART in patients with TB. Rationale For ART Initiation Most HIV infected persons enjoy long periods of normal health before the virus overwhelms the immune system and starts to cause ill health. It is now accepted that ART should not be initiated too early in the course of the infection. On the other hand, treatment should not be delayed too long, such that the immune system is so severely destroyed as to make it difficult to recover, or until the patient s quality of life is compromised. In general, it is opportunistic infections that cause the majority of morbidity in people with HIV and these should be aggressively treated before even considering ARVs. For example, a patient with TB, severe pneumonia or cryptococcal meningitis, who is only given ARV therapy, will almost certainly die. 16

21 The clinical benefits of taking ARV drugs are usually not apparent until six to eight weeks after commencing the therapy. Consequently, starting lifelong ARV therapy should not be seen as an emergency measure. The decision to start therapy should therefore be based on sound medical and social criteria. Next we shall look at the criteria for starting ARV therapy. Table 2.1 outlines the recognised advantages and risk of delaying ARV treatment. Table 2.1: Potential risks and benefits of delaying ART Benefits of delayed therapy To avoid development of side effects which develop from long-term use of ARVs; To delay the development of resistant virus, with the attendant risk of transmission of drug resistant virus; To delay the occurrence of treatment failure as a result of resistant virus in a healthy patient, necessitating the use of potentially toxic or expensive ARVs; Adherence to treatment is more difficult to maintain in a relatively well patient over prolonged duration of treatment. Risks of delayed therapy Possible risk of irreversible immune system damage; The increased possibility of progression to AIDS. Starting ARV therapy is not an emergency! So what criteria should one use to start ARV therapy? Lets look at that next. Criteria for Starting ARV Therapy In Module 1, you learnt about the WHO Staging of HIV. Can you recall the various stages of HIV infection? It is normally not necessary to memorize what ailments constitute which WHO stage, but it recommended that you have a wall chart or table-top reference that you can consult each time you examine HIV infected patients. There are two main criteria used to start ART. These are medical and social criteria. 17

22 Medical Criteria The medical criteria monitors the strength of a persons immune system (CD4 testing) also known as immunological monitoring. Immunological monitoring provides the most reliable information on the immune status of the patient, and therefore, is the ideal way of determining who should be started on ART. The table below provides guidance on what action should be taken at various CD4 levels. Table 2.2: Immunological Monitoring for ART Initiation CD4 (cells/ml) Treatment Recommendation Subsequent action <200 Initiate ART Carry out a CD4 test at 3 months and then every 6 months thereafter Consider treatment, particularly in case of pulmonary tuberculosis or history of severe bacterial infection. Initiate ART before CD4 falls below 200 cells/ml If ART not initiated, CD4 test every 3 months. If ART initiated, CD4 test at 3 months and then every 6 months thereafter. >350 Continue other care: Cotrimoxazole prophylaxis, nutrition and hygiene, immunization, safer sex, psychosocial support etc CD4 test every 6 months, or as indicated by the clinical condition of the patient. You should only start HIV-infected adults and adolescents on antiretroviral treatment under the following conditions: If CD4 testing is available, it is recommended to document baseline CD4 counts and to offer ART to patients with: WHO Stage IV disease, irrespective of CD4 cell count; WHO Stage III disease if CD4 cell counts is less than <350/mm 3 CD4 is less than 250 at any stage Though CD4 testing provides the ideal criteria for initiation of ART, the test is expensive to perform and may not be available in most primary care facilities. Clinical staging, however, can be used to guide decisions on when to start ART, where CD4 testing is not available. 18

23 If CD4 testing is not available, it is recommended to offer ART to patients with: WHO Stage IV disease, irrespective of total lymphocyte count; WHO Stage III disease (including but not restricted to HIV wasting, chronic diarrhoea of unknown etiology, prolonged fever of unknown etiology, pulmonary TB, recurrent invasive bacterial infections or recurrent/persistent mucosal candidiasis), irrespective of the total lymphocyte count; WHO Stage II disease with total lymphocyte count of less or equal to 1200mm cubed. Social Criteria This criteria determines that the patient (or parent/guardian if patient is a child) is able or willing to: demonstrate an understanding of the importance of strict, long term adherence to therapy and monthly attendance of the clinic; afford the cost of the drugs and investigations on a LONG TERM basis (if in a cost recovery program); identify a treatment assistant (family member or a friend) to support them with adherence to therapy; disclose their contact details and physical address (Patient Locator Card ) and be contacted when they miss appointments; commit themselves to safer sex practices. In addition to the above criteria, there are other requirements for starting ARV therapy. Let us discuss them too. Other Requirements for Starting ART If you work at a primary facility, there are other requirements that you should consider before starting ART. These are as follows: 1. HIV positive patient has a written documented HIV test; 2. Patient fits criteria to be started, if all the 7 questions have a negative response; 3. Opportunistic infections have been treated or stabilised; 4. Patient is ready for ARV therapy; 19

24 5. A supportive clinical team that is well prepared for chronic care; 6. There is a reliable drug supply. We shall discuss each in turn. HIV positive patient with a written documented HIV test; According to the MOH guidelines, you should only start ARV in patients who have written documentation of a positive HIV test. If the patient has had a positive HIV test at another facility, but does not have written documentation, the test should be repeated. Do not start patients on ART if there is only a clinical suspicion of HIV infection. There is a possibility that a few patients may want to get ARV drugs to sell them. Also in the past, mistakes have also been made in assuming that a patient with severe wasting has AIDS. Yet, as you know other conditions like TB can also cause severe wasting in adults. So it is important to have adequate proof before you initiate ARTs. Patient fits criteria to be started on ART, if you can answer NO to the following questions; Does the patient have a severe illness requiring referral or a WHO stage 4 condition? You should not initiate ART during a severe acute opportunistic infection or other severe illness as it can cause a strong reaction with the opportunistic infection, thus making the symptoms suddenly worsen, and the patient can even die Is the patient currently on TB treatment? Although TB is accorded a special treatment unlike other OIs, you should not give ART and TB drugs together unless you are able to assess interactions with the current regimen. Is there peripheral neuropathy? Patients with burning or tingling or numbness in the feet or hands should not receive d4t which causes nerve toxicity, because this may worsen the problem of tingling and numbness. Is there jaundice or known liver disease? Patients with liver disease will need an adapted regimen and should not receive a regimen that contains drugs that can cause liver toxicity, like nevirapine. 20

25 Does the patient have a chronic disease like diabetes or heart disease? Patients with a chronic disease should be referred to a senior clinician as they require more expertise in deciding how to give ART. Is the patient a child? ART initiation in children needs to be done by a qualified clinician who understands how to read their CD4 values and knows the correct ARV drugs and dosing. So if you do not have this expertise you should refer the child immediately. Is there prior ART use (including Nevirapine for prevention of mother-to-child transmission)? You should always take a history of what kind of medication patients took before, especially ARV drugs. This will help you to determine the most suitable regimen for that patient and identify drugs that they are probably resistant to. Opportunistic infections have been treated or stabilised; As we have mentioned several times, any patient with severe illness should be treated first before being put on ARV. There are a few exceptions however, such as patients on TB treatment and those with OIs such as prurigo and diarrhoea which do not respond to any other treatment other than ARVs. The Patient is ready for ARV therapy; ARV treatment is not an emergency. It is very important that a partnership is formed between the clinician and the patient where they take responsibility for taking ARV drugs regularly. A Supportive clinical team is prepared for chronic care; Providing care for PLWHA requires a team approach. Do not be a lone ranger! If you are a clinician you will need to work with counsellors and lay providers to provide treatment education and support, someone to dispense the drugs correctly, and community health workers for home-based care. 21

26 There is a reliable drug supply Continuous levels of ARV drugs are needed to halt the virus making new copies. Patients who stop and start treatment may develop ARV drug resistance and treatment failure. You should therefore ensure that you have a reliable drug supply. Figure 2.1 outlines what you should consider when commencing ARV therapy for adults and adolescents. Institutional Requirements for Initiating an ART Program. Are there institutional requirements for starting an ART program? Before you read on do the following activity. It should take 5 minutes to complete. ACTIVITY List some of the requirements that you believe should be met by institutions before they start an ART programme. Well done! I believe your answer included some of the following requirements for starting an Antiretroviral Treatment Program: Availability of quality HIV testing services (voluntary, diagnostic as well as routine counselling and testing); Availability of quality antiretroviral drugs on long-term basis; Assurance of an adequate supply and storage of drugs, including drugs for treatment of opportunistic infections and other HIV related conditions; Availability of a trained multidisciplinary team, including doctors, nurses, counsellors, social workers etc; 22

27 Availability of a system for training, continuous education, monitoring, support supervision and feedback on safe and effective management of HIV disease and antiretroviral treatment; Capacity to recognize and appropriately manage common HIV related conditions; Reliable laboratory monitoring services including routine haematological and biochemical tests for detection of drug toxicity. Figure 2.1: ARV commencement algorithm for adults and adolescents. (Source: MOH, 2006) 23

28 Patient Assessment and Education Prior to ART Initiation Before any patient is started on antiretroviral therapy, they should undergo baseline clinical assessment and receive thorough education about how ART works and how to maintain adherence. Baseline Clinical Assessment A basic clinical assessment should include the following: A complete medical history; Physical examination; Laboratory investigations; Patient education and counselling; Taking a complete Medical History Once again, lets start with your thoughts on this. Complete the following activity before you read on. ACTIVITY What information would you gather when taking a complete medical history? Now read through the text below and see if your ideas are included. The complete medical history should include the following: Essential demographic characteristics, such as age, marital status, etc; The past medical history including major illness (particularly TB), hospitalization and surgeries; 24

29 The length of time since HIV diagnosis; Current medication and symptoms; In the case of women, you should review the current or planned pregnancy and access to contraceptive services. Physical Examination It is important to carry out a baseline physical examination. This should include: Vital signs and weight; Examination of the skin and mouth, oral pharynx, lymph nodes and extremities; Examination of the lungs, heart, abdomen, nervous system, eyes, and genital tract. Laboratory Investigation The following table outlines the recommended investigations before initiating, and for monitoring ART. Table 2.3: Recommended Laboratory Investigation before initiating ART I. Absolute minimum INVESTIGATION HIV antibody test LEVEL AVAILABLE All levels OBJECTIVE Diagnose HIV and initiate comprehensive care FREQUENCY Before ART II. Basic Recommended tests Hemoglobin Total WBC + differential All levels All levels Monitor degree of anemia if severe transfuse before ART or use D4T instead of Zidovudine. Monitoring neutropenic side effects. Lymphocyte count where CD4 machine is not available If on AZT do at baseline, 2 weeks, then monthly If not AZT baseline and then every 6 months and when indicated. 6 monthly LFTs: Alanine(ALT) or aspartate (AST)aminotransferase Serum creatinine and or urea District hospitals District hospitals Monitor hepatitis co- infection and hepatotoxicity Monitor renal function Do at baseline, at 2weeks, then monthly especially if Nevirapine is used. 6 monthly and when indicated Serum glucose District hospitals Monitor hyperglycemia in When indicated 25

30 patients on protease inhibitors III. Desirable test Pregnancy test Serum lipids All levels District hospitals plus referral hospital Change therapy to appropriate regimen Monitoring hyperlipidemia for those on protease inhibitors At base line and when indicated for all women of child bearing potential When indicated CD4 cell count Few regional hospitals Monitoring immune response to therapy At baseline and then 6-12 monthly Patient Education Prior to ART Initiation The initiation of ART should not be rushed. Remember it is not an emergency! Before you start your patients on ART you should prepare them adequately. Patient education and counselling is particularly important and should cover the following topics: How HIV infection affects the body; Prophylaxis and multivitamin supplementation; Antiretroviral Drugs; Arrangements of how patient will come for appointments ; Review patient s willingness to start ART; Community Links and Patient Support Groups. Let s briefly discuss each point looking at the information that you should give to the patient. How HIV infection affects the body? You should inform the patient that HIV attacks the body s immune system and weakens the body s ability to fight off infections. Once the body s immunity is weakened, one becomes vulnerable to infections that they would normally fight off. These are called opportunistic infections. Most of these infections are treatable. The patient should seek early medical attention anytime they feel unwell. You should inform patients of their CD4 cell count and the importance of closely monitoring them to ensure their body defence is still working. 26

31 Prophylaxis and multivitamin supplementation. Arrange for nutritional assessment and counselling and inform the patient that they can reduce their chances of developing opportunistic infections by taking cotrimoxazole on a daily basis, maintaining good nutrition and providing multivitamin tablets. These measures would keep them healthy and strong for longer. Antiretroviral Drugs: Inform the patient that antiretroviral drugs are strong medicines that fight HIV in the body and prevent the virus from destroying the body s immune system. These drugs are lifesaving drugs and patient s health depends on taking them every day at the right time; do NOT cure HIV; do not prevent HIV transmission to others the patient must still use condoms and practice safer sex; may interact with other drugs: the patient should not take herbal medicines or over-thecounter medicines before discussing with a health care worker. Antiretroviral drugs stop HIV from multiplying in the body, therefore, treatment with these drugs is life-long. Demonstrate to the patient, the drug regimen with the actual drugs and show them how they should take them. Discuss possible side effects of the drugs and tell the patient what to do if they occur. Adherence and Follow-Up: Inform the patient of need to return to the clinic on the scheduled dates so that you can ensure that their medicines are working properly and that there are no side effects. Emphasize the importance of adherence and tell the patient that ARVs will only work properly if taken as prescribed. Missing doses, even occasionally, makes treatment ineffective, and can result in treatment failure with recurrence of illness, opportunistic infections and even death. Ask the patient what they intend to do to ensure that they do not miss taking their medicines? 27

32 Assess Adherence Strategies: Ask them to identify either a member of family, friend or community health worker who can remind them to take their medication. This person should be identified and also be educated on ART. Teach the patient pill cues such as putting the tablets next to toothbrush; using a pill diary; alarm clock in the watch or phone. Arrangements of How Patient Will Come for Appointments: If the patient does not leave near your health facility and it is not convenient for them to commute to and from their home, refer them to the health facility nearest their home that offers ART service. Review patient s willingness to start ART: Has the patient demonstrated ability to keep appointments, or to adhere to other medications? Has the patient disclosed his or her HIV status? If not, encourage them to do so. Disclosure to at least 1 person who can be the treatment supporter is important. Does the patient want treatment and understand what this treatment is for? Is the patient willing and able to come for the required clinic follow-up? Community Links and Patient Support Groups: Advise patient on available community support groups and facilitate contact. Discuss the importance of disclosure especially to partners who may be at risk of continued exposure to HIV. Disclosure to a treatment supporter may be crucial in ensuring adherence and in providing emotional support. Discuss, encourage and facilitate testing of exposed individuals in the family and/or among sexual contacts. Continuing Counselling and Support: Always make time for patients to raise issues of concern to themselves that may require counselling and support. After you conduct a thorough baseline clinical assessment, then you can now select an appropriate ARV regimen. 28

33 Choosing a ARV Regimen Fighting the HIV virus requires a smart approach as the virus seems very clever. It needs a combined force or what is called combination therapy. It takes a combination of 3 different drugs to stop HIV from replicating and making new copies of itself rapidly. This approach offers maximum benefits with regards to providing maximum and durable viral suppression without producing unacceptable side effects. This principle has been used by the World Health Organization and many national HIV/AIDS programmes have provided guidelines on standardized ARV regimens. Why should we use standard treatment regimens? The reasons for using standardized treatment regimens include: The need to provide treatment to large numbers of PLWAs in an affordable, accessible and simplified manner; To simplify prescribing and prevent misuse of these potentially life-saving medicines; By restricting the use of ARVs to first line, second line and so on, certain ARVs are protected for use on later occasions as regimens begin to fail; To simplify procurement and supply of these ARVs; Drug combinations can be formulated as fixed dose combinations further simplifying prescribing and encouraging adherence. The powerful combination of 3 different antiretroviral drugs is called Highly Active Retroviral Therapy or HAART. This is the standard for good therapy and has the greatest benefits for the longest time. There are two different types of ART regimens used in the world. These are the 1 st line and second line ART regimens. Lets look at each type in turn. 29

34 First-line and Second-line ART Regimens A first-line regimen is a combination of drugs that are used in a patient who has no prior ART experience. This means that the patient has never taken ARV drugs before. Most commonly, a first-line regimen will consist of two NRTIs and one NNRTI. The following are the 4 different first-line combinations that can be given: d4t-3tc-nvp d4t-3tc-efv AZT-3TC-NVP AZT-3TC-EFV Tables 2.4 shows the standard or first-line regimen. Table 2.4: Standard 1 st Line Regime for Adults and Adolescents Stavudine Stavudine Zidovudine Zidovudine (D4T) (D4T) (AZT) (AZT) Lamivudine or Lamivudine or Lamivudine or Lamivudine (3TC) (3TC) (3TC) (3TC) Nevirapine (NVP) Efavirenz (EFV) Nevirapine (NVP) Efavirenz (EFV) Did you notice anything peculiar about these regimens? I hope you noted the following: That 3TC is included in all 4 regimens. The first drug is either d4t or AZT (but not both together). The last drug is NVP or EFV (not both together). AZT is the same as ZDV. ARTs are always given in a combination of 3 drugs. 30

35 If well tolerated with good adherence, the patients can take the first-line treatment for several years. However, some patients eventually develop treatment failure. This means that the first-line treatment is not effective anymore. Treatment failure often occurs because of non-adherence, that is, the drugs were not taken correctly. In patients who develop treatment failure, the clinician may decide to switch to a second-line regimen. The second-line regimen consist of 2 NRTIs + 1 PI. The second-line regimen involves taking more pills, it sometimes has food restrictions and often has more side effects than first-line regimens. Even second-line regimen can fail, if the patients do not adhere well. Table 2.5 shows the drugs used in the second line regimen. Table 2.5: Standard 2 nd Line Regime for Adults and Adolescents Zidovudine Zidovudine + + Didanosine or Didanosine + + Lopinavir/Ritonavir Nelfivanir Correct Dosage of Antiretroviral Drugs The usual adult and adolescent dose of the following1 st line antiretroviral drugs is as follows: Nevirapine (200mg) OD for 2 weeks then 200mg BD (first 2 weeks, it is necessary to use separate tablets) Stavudine(d4T) 30 mg BD Lamivudine (3TC) 150mg BD 31

36 As you can see, Nevirapine requires an escalating dose once daily for two weeks, then twice daily. These tablets are available in separate tablets or in fixed-dose combination tablets. A fixed-dose combination tablets is a tablet that contains all the 3 drugs. Thus in the case of the drugs listed above, there would be one tablet with 30 mg of d4t plus 150 mg of 3TC and 200 mg of NVP. Table 2.6 Dosage of antiretroviral drugs used in the first-line ARV regimens. (Source, MOH, 2006) Drug Dose Note: same dose for all adolescents and adults Same dose for adults regardless of weight zidovudine (AZT) lamivudine (3TC) nevirapine (NVP) efavirenz (EFV) stavudine (d4t) 300 mg twice daily 150 mg twice daily 200 mg once daily for 14 days, thereafter 200 mg twice daily 600 mg once daily 30 mg twice daily As you can see in Table 2.6, in the case of nevirapine, during the first two weeks of commencing treatment, it is given in a lower dose of 200mg once daily. Then after the second week the dosage becomes 200mg twice daily. This is known as an escalating dose or lead-in dose. Why is Nevirapine given in an escalating dose? Nevirapine is given in an escalating dose to reduce its side effects. If it is given twice a day in the first two weeks it can result in a serious rash or liver problems. Therefore, in the first two weeks the patient should take the drugs as follows: 1 fixed-dose combination tablet of d4t-3tc-nvp in the morning, 1 tablet of d4t and 1 tablet of 3TC in the evening. Sometimes both d4t and 3TC come in a single fixed-dose tablet. Then after the first 2 weeks, the patient should take 1 fixed-dose combination tablet in the morning and one fixed-dose combination tablet in the evening. 32

37 For the first 2 weeks of treatment, the patient should receive 14 fixed-dose combination tablets d4t-3tc-nvp in one, 14 tablets of d4t, and 14 tablets of 3TC OR For the first 2 weeks of treatment, the patient should receive 14 fixed-dose combination tablets d4t-3tc-nvp in one and 14 tablets of fixed-dose combination tablets of d4t-3tc in one. You now know what combination therapy you can give for 1st line and second line ART. Let us now look at what you should not give and some of the few cases where you can make an exception (see Table 2.7). Table 2.7: Antiretroviral regimens or components that should not be offered at any time Antiretroviral regimen or component Mono or dual therapy Stavudine + Zidovudine Didanosine + stavudine Lamivudine + zalcitabine Atazanavir + indinavir Efavirenz in pregnancy and in women with significant child bearing potential Rationale It facilitates Rapid development of resistance Inferior antiretroviral activity when compared to combination with three or more antiretrovirals Antagonistics effects on HIV 1 High incidence of toxicities-lactic acidosis (especially in pregnant women), peripheral neuropathy, pancreatitis etc In-vitro antagonism Potential additive hyperbilirubinemia Potential teratogenicity Exception Pregnant women may be given mono or dual therapy for the purpose of prevention of mother transmission of HIV (PMTCT) No exception When no other options are available and potential benefits outweigh the risks. No exception No exception When no other options are available and potential benefits outweigh the risks 33